Recent work has emphasized the importance of proliferating, endothelial cells in the pathogenesis of pulmonary arterial hypertension (PAH). We have proposed studying the disease process of PAH on two complimentary fronts. First, we have explored the potential role of peripheral blood cells as biomarkers of disease in PAH. We have successfully demonstrated significant and predictive alterations in the gene expression of circulating mononuclear cells in patients with PAH compared to normal controls. We have also found increased numbers of endothelial precursor cells within the peripheral blood of these patients. Our second approach to this disease has focused on mechanisms responsible for the endothelial cell proliferation. We have recently reported evidence of human Herpesvirus-8 (HHV-8) infection within the pulmonary vascular endothelial cells of patients with idiopathic pulmonary arterial hypertension. We speculate that HHV-8 infection plays a causative role in the endothelial cell proliferation characteristic of this disease. We now propose to expand upon these important preliminary findings. First, we wish to further define the relevance and importance of peripheral blood cell gene expression as a biomarker of pulmonary arterial hypertension. Second, we wish to investigate the effect of HHV-8 infection on cultured pulmonary microvascular endothelial cells as well as on circulating endothelial precursor cells from patients with idiopathic pulmonary arterial hypertension (IPAH/PPH). The specific aims of this project are: 1) Develop discrimination models using gene microarrays of peripheral blood mononuclear cells which distinguish patients with IPAH/PPH from patients with pulmonary hypertension related to the CREST variant of scleroderma. 2) Evaluate the effect on cell growth, apoptosis and global gene expression of HHV-8 infection in human pulmonary microvascular endothelial cells, blood outgrowth endothelial cells and endothelial precursor cells from patients with PAH.